Olefination process to itaconate and succinate derivatives

ABSTRACT

An efficient and selective process, capable of scale-up, to make itaconate derivatives of formula (IV), and/or succinate derivatives of formula (V) and/or (VI) by asymmetric hydrogenation of the itaconate derivatives.                    
     wherein R, R 1  and R 2  are as defined herein.

This is a divisional application of U.S. application Ser. No.09/977,822, now U.S. Pat. No. 6,452,041, filed Oct. 15, 2001, whichclaims the benefit of U.S. Provisional Patent Application No.60/253,434, filed Nov. 28, 2000 and U.K. Patent Application No.0025310.4, filed Oct. 16, 2000, all of the aforementioned applicationsare hereby incorporated by reference in their entirety.

The invention described herein relates to a novel olefination processwhich is useful for making certain itaconate and succinate derivatives.

It is desirable in a number of instances to be able to have an efficientand selective process, capable of scale-up, to make itaconatederivatives of formula (I), and/or succinate derivatives of formula (II)and/or (III):

wherein “R*” is a sterically bulky group.

Of particular interest to us is the provision of compounds of theformula (IV), (V) and (VI), especially (IV) and (V):

wherein R is aryl, C₃₋₈ cycloalkyl, C₁₋₁₀ alkyl, (aryl)C₁₋₁₀ alkylene,(C₃₋₈ cycloalkyl)C₁₋₁₀ alkylene, heterocyclyl, (heterocyclyl)C₁₋₁₀alkylene, (aryl)C₃₋₈ cycloalkylene, (C₃₋₈ cycloalkyl)arylene or (C₁₋₁₀alkylaryl)C₁₋₁₀ alkylene,

wherein “aryl” is a mono- or bicyclic partially or fully unsaturatedcarbocyclic ring system containing from 4 to 10 atoms, such as phenyl ornaphthyl, or a partially or fully unsaturated mono- or bicyclicheterocyclic moiety having up to 10 atoms in the ring system and with upto 4 hetero-atoms in the said ring system each independently selectedfrom N, O and S, said carbocyclic ring system and heterocyclic moietybeing optionally substituted by one or more substituents eachindependently selected from halogen, NO₂, NH₂, CO₂R⁹, phenyl, C₁₋₆alkyl(optionally substituted by one or more halogen), and C₁₋₆alkoxy(optionally substituted by one or more halogen), and“heterocyclyl” is a 3- to 8-membered mono or bicyclic saturatedheterocyclic group having from 1 to 4 ring hetero-atoms eachindependently selected from N, O and S, optionally substituted by one ormore substituents each independently selected from halogen, NO₂, NH₂,CO₂R⁹, phenyl, C₁₋₆ alkyl(optionally substituted by one or morehalogen), and C₁₋₆ alkoxy(optionally substituted by one or morehalogen);

R¹ is C₁₋₆ alkoxy,

R² is OH or O⁻M⁺;

R⁹ is H or C₁₋₆ alkyl; and M⁺ is the cation of a metal such as sodium,lithium or potassium, or is a protonated amine moiety such as (mono-,di- or tri-C₁₋₁₀ alkyl)ammonium, (mono-, di- or tri-C₃₋₁₀cycloalkyl)ammonium, (C₁₋₁₀ alkyl)_(n1) (C₃₋₁₀ cycloalkyl)_(n2)ammonium,anilinium, benzylammonium, triethanolammonium, or(S)-α-methylbenzylammonium, where n1 and n2 are each independentlyselected from 1 or 2 with the proviso that the sum of n1 and n2 is notgreater than 3;

Alkyl groups, and groups containing alkyl moieties such as alkoxy andalkylene groups, can be straight chain or branched if the number ofcarbon atoms allows,

Halogen means fluorine, chlorine or bromine,

Cycloalkyl groups attached to an ammonium moiety can contain 1, 2, or 3rings, where the number of carbon atoms allows, for exampleadamantanammonium.

Production of compounds related to (IV), (V) and (VI) has been disclosedpreviously, e.g. by Owton et al, in Synthetic Communications, 23(15),2119-2125 (1993), M J Burk et al, Angew. Chem. Int. Edn. (Eng.) (1998)37, 13/14, 1931-1933, Monsanto, U.S. Pat. No. 4,939,288, and byChirotech Technology Ltd. in International Patent Applicationpublication no. WO 99/31041. Known olefination reactions leading tosystems related to (IV), generally result in poor E/Z selectivity, (fora review of the Stobbe condensation, see Org. React. 1951, 6, 1-73).Where selectivity has been controlled, however, for example by the useof phosphorus reagents, the substitution pattern is different from thatrequired by us in formula (IV)(e.g. Monsanto, Owten, supra).

The products of the Owten chemistry are exemplified by compounds of theformula (VII):

on which we attempted hydrolysis of the ethyl ester using conventionalchemistry. In our hands this resulted in scrambling of the olefinicmoiety resulting overall in a mixture of stereoisomers and regioisomers.

Use of the Monsanto chemistry gives products of the formula (VIII):

which has the wrong substitution pattern for our requirements.

We have discovered a new and efficient olefination method which can beused to make compounds of formula (IV) in good yield and with goodtrans-selectivity, and which products can then be asymmetrically reducedto give compounds of formula (V) and (VI). The olefination isbase-catalysed and can be used with enolisable aldehydes or aldehydederivatives without significant amounts of self-condensation products.We also surprisingly observe no substantial double bond migration togive deconjugated isomers of (IV) under the basic conditions, whichwould afford other geometric and regio-isomers, which is anothersignificant problem with similar prior art olefinations.

Our olefination system is thus particularly useful when highly selectiveproduction of the compounds (IV), (V) and/or (VI) is required, or whereseparation of (IV), (V) and/or (VI) and/or the respective isomersthereof, may be difficult or undesirable, such as in processing to makepharmaceutical products and regulatory starting materials for suchproducts.

Thus, according to the present invention, there is provided a processfor the preparation of compounds of formula (IV) as defined above,comprising reaction of an aldehyde of formula RCHO, or a protectedderivative thereof such as a hemiacetal or adduct thereof such as abisulphite, wherein R is as defined above, with a phosphorus compound offormula (IX):

or a metal carboxylate salt thereof such as a sodium, lithium orpotassium carboxylate salt thereof,

wherein R¹ is as defined above, and

“P” is a phosphonate moiety of formula —P(O)(OR³)(OR⁴), wherein R³ andR⁴ are either each independently selected from H, C₁₋₆ alkyl, benzyl andphenyl (optionally substituted by one or more C₁₋₆ alkyl), or R³ and R⁴taken together are C₂₋₅ alkylene,

or “P” is a phosphorane moiety of formula —(PR⁵R⁶R⁷)⁺X⁻ wherein R⁵, R⁶and R⁷ are each independently selected from C₁₋₆ alkyl and phenyl, and Xis bromine, chlorine or iodine, in the presence of a sodium, lithium orpotassium C₁-C₆ alkoxide base, in an inert solvent, and at a temperatureof from −80° C. to 20° C.

Preferably the reaction time is less than 24 hours.

Preferably R is (aryl)C₁₋₁₀ alkylene or (C₃₋₈ cycloalkyl)C₁₋₁₀ alkylene.

More preferably R is phenylethyl, cyclohexylethyl or(2-methyl-1,1′-biphenyl-4-yl)ethyl.

Preferably R¹ is t-butoxy.

Preferably R² is OH, O⁻Li⁺, O⁻Na⁺, O⁻K⁺, O⁻cyclohexylammonium⁺,O⁻adamantanammonium⁺, O⁻triethanolammonium⁺ orO⁻(S)-α-methylbenzylammonium⁺.

Preferably the olefination reaction is carried out using the aldehydeRCHO or the sodium bisulphite adduct thereof RCH(OH)SO₃ ⁻Na⁺.

Preferably “P” is P(O)(OC₂H₅)₂, P(O)(OCH₂CH₂O) or a triphenylphosphiniumhalide moiety.

More preferably P is P(O)(OC₂H₅)₂.

Preferably the base is potassium t-butoxide, sodium t-butoxide or sodiummethoxide.

When the base alkoxide and R¹ are different there is a possibility oftransesterification taking place during the olefination reaction. Wehave found that this apparently has no detrimental effect on the courseof the reaction at the olefination centre, in terms of stereochemistry,and may not be important with respect to the use made of the product,e.g. if it is used as an intermediate and the R¹ moiety is laterremoved, e.g. by displacement, hydrolysis or deprotection.

Preferably the olefination reaction solvent is anhydroustetrahydrofuran, anhydrous toluene or R¹H, where R¹ takes the meaning asspecified above with respect to the compounds of formulae (IV), (V) and(VI), or a mixture thereof.

More preferably the reaction solvent is selected from tetrahydrofuranand toluene when the aldehyde RCHO is used as a substrate, and selectedfrom tetrahydrofuran/t-butanol and toluene when the bisulphite adduct isused as substrate.

Preferably the reaction is carried out at a temperature from −20° C. to10° C.

More preferably the reaction is carried out at a temperature from −10°C. to 10° C.

Most preferably the reaction is carried out at a temperature from 0° C.to 5°0 C.

When the aldehyde RCHO is used as substrate, it is preferable to add thephosphorus compound to the base/solvent mixture, followed by addition ofthe aldehyde. Alternatively, the phosphorus compound and aldehyde arecombined, then the base is added. A further alternative is to add thebase to the phosphorus compound followed by addition of the aldehyde.

When the bisulphite is used as the substrate, it is preferable to addthe base to a mixture of the bisulphite adduct and the phosphoruscompound, or, alternatively, the bisulphite is added to a mixture of thephosphorus compound and the base.

‘Bisulphite’ or ‘bisulphite adduct’ is taken to mean anα-hydroxysulphonate, which is the product of the reaction of an aldehydewith sodium, potassium or lithium bisulphite. Other suitable bisulphitesare known in the art.

The skilled person will appreciate that the substrates, and startingmaterial of formula (IX), can be obtained from commercial sources, ormade by methods known in the art, e.g. by adaptation of the methodsherein described in the sections below, and/or adaptation thereof, forexample by methods known in the art. Suitable guides to synthesis,functional group transformations, use of protecting groups, etc. arefound in standard organic chemistry textbooks, for example,“Comprehensive Organic Transformations” by R C Larock, VCH PublishersInc. (1989), “Advanced Organic Chemistry” by J March, Wiley Interscience(1985), “Designing Organic Synthesis” by S Warren, Wiley Interscience(1978), “Organic Synthesis—The Disconnection Approach” by S Warren,Wiley Interscience (1982), “Guidebook to Organic Synthesis” by R KMackie and D M Smith, Longman (1982), “Protective Groups in OrganicSynthesis” by T W Greene and PGM Wuts, John Wiley and Sons Inc. (1999),and P J Kocienski, in “Protecting Groups”, Georg Thieme Vedag (1994),and any updated versions of said standard works.

The above olefination process is optionally followed by conversion ofthe product of formula (IV) where R² is O⁻M⁺ wherein M⁺ is a metal suchas Na, Li or K, to a compound of formula (IV) where R² is OH bytreatment with a proton source, which may optionally be converted to acompound of formula (IV) wherein R² is O⁻M⁺(where M⁺ is a protonatedamine moiety as previously defined), by treatment with a correspondingamine.

A further aspect of the invention is the asymmetric hydrogenation ofitaconate compounds of the formula (IV) to give succinate compounds ofthe formula (V) or (VI).

Asymmetric hydrogenation of compounds of formula (IV) may be achieved ina multitude of ways, including methods known in the art. For example usemay be made of catalytic hydrogenation using chiral rhodium or rutheniumcomplex of an optically active biphosphine or biphosphinite compoundsuch as(4R,5R)-(−)-O-sopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane[(R,R)-DIOP], (R,R)-(−)-1,2-Bis[(O-methoxyphenyl)(phenyl)phosphino]ethane [(R,R)-DIPAMP],(−)-(R)-N,N-Dimethyl-1-((S)-1′,2-Bis(Diphenylphosphino)ferrocenyl)ethylamine[(R)-(S)-BPPFA],(−)-(2S,4S)-2-Diphenylphosphinomethyl-4-diphenylphosphino-1-t-butoxycarbonylpyrrolidine[(S,S)-BPPM], (2S,3S)-(−)-Bis(diphenylphosphino)butane[(S,S)-CHIRAPHOS], R-(+)-1,2-Bis(diphenylphosphino)propane[(R)-PROPHOS],(2R,3R)-(−)-2,3-Bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene [(R,R)-NORPHOS], (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl[(R)-BINAP], (R)-1,2-bis(diphenylphosphino)-1-cyclohexylethane[(R)-CYCPHOS], (2R,4R)-(+)-2,4-Bis(diphenylphosphino)pentane[(R,R)-BDPP], N-benzyl-(3R,4 R)-3,4-bis(diphenylphosphino)pyrrolidine[(R,R)-DEGPHOS], (−)-1,2-Bis((2R,5R)-2,5-dimethylphospholano)benzene[(R,R)-Me-DUPHOS], (-)-1,2-Bis((2R,5R)-2,5-diethylphospholano)benzene[(R,R)-Et-DUPHOS],N,N′-bis[(R)-(+)-a-methylbenzyl]-N,N′-bis(diphenylphosphino)ethylenediamine[(R)-PNNP],(R)-(−)-2,2′-bis(dicyclohexylphosphino)-6,6′-dimethyl-1,1′-biphenyl[(R)-BICHEP], (1R,2S,4R,5S)-2,5-dimethyl-7-phosphadicyclo[2.2.1]heptane[(R, S, R, S)-Me-PENNPHOS),(2S,2′S)-Bis(diphenylphosphino)-(1S,1′S)-bicyclopentane [(S,S)-BICP],1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene [(S,S)-Et-FerroTANE],(R, R)-1,2-bis(di-t-butylmethylphosphino)methane[(R,R)-t-butyl-miniPHOS],(R)-(+)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl [(R)-tol-BINAP],(R)-(+)2-(Diphenylphosphino)-2′-methoxy-1,1′-binaphthyl [(R)-MOP],(R)-(+)-1-(2-Diphenyiphosphino-1-naphthyl)isoquinoline [(R)-QUINAP],Methylα-D-glucopyranoside-2,6-dibenzoate-3,4-di(bis(3,5-dimethylphenyl)phosphinite)(CARBOPHOS),(R)-(−)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine[(R)-(S)-JOSIPHOS],(R)-(−)-4,12-Bis(diphenylphosphino)-[2.2]-paracyclophane[(R)-PHANEPHOS],(R)-(6,6′-Dimethoxybiphenyl-2,2-diyl)-bis(diphenylphosphine)[(R)-MeO-BIPHEP], ],(R)-(6-Chloro-6′-methoxybiphenyl-2,2-diyl)-bis(diphenylphosphine)[(R)-Cl-MeO-BIPHEP] or 2,2′-bis(diphenylphosphino)-4,4′,6,6′-tetrakis(trifluoromethyl)-1,1′-biphenyl (BIFUP) which arewell-known to the skilled chemist working in the asymmetrichydrogenation art.

It is to be appreciated that other examples include related structures,such as those with alternative alkyl substituents, and stereoisomers ofthe above-mentioned examples.

Some catalysts are mentioned in the Examples, and other suitablecatalysts which may be useful are mentioned in the followingpublications and references therein, all of which are hereinincorporated by reference in their entirety:

U.S. Pat. No. 4,939,288 (Monsanto); International Patent Applicationpublication no. WO 98/02445 (Chiroscience Ltd);

International Patent Application publication no. WO 99/31041 (ChirotechTechnology Ltd);

European Patent Application 0 673 911 Al (Takasago InternationalCorporation);

International Patent Application publication no. WO 00/27855(Chiroscience Technology Ltd);

X. Zhang, Enantiomer (1999), 4(6), 541;

H. Tye, JCS Perkin I, (2000) (3) 275-298;

J. M. Brown, Compr. Asymmetric Catal. I-III (1999), 1, 121-182;

M. J. Burk, Spec. Chem. (1998) 18(2) 58-59, 62;

T. Yamagishi, Organomet. News (1995) (4), 113-118;

J. P. Genet, ACS Symp. Ser. (1996) 641 (Reductions in OrganicSynthesis), 31-51;

H. Kumobayashi, Recl. Trav. Chim. Pays-Bas (1996) 115(4) 201-210;

M. J. Burk et al, Pure Appl. Chem. (1996) 68(1) 3744;

H. Takaya et al, Catal. Asymm. Synth. (1993) 1-39;

S. Akutagawa, Chirality Ind. (1992) 325-339; A. Borner et al, TransitionMet. Org. Synth. (1998) 2, 3-13;

D. G. Blackmond, CATTECH (1998) 2(1), 17-32;

R. Noyori, Acc. Chem. Res. (1997) 30(2) 97-102;

W. S. Knowles, Chem. Ind.(Dekker) (1996) 68(Catalysis of OrganicReactions) 141-152;

U. Behrens, Spec. Chem.(1996) 16(5) 174, 176-177;

R. Noyori, Acta Chem. Scand. (1996) 50(4), 380-390;

H. B. Kagan, Mec., Phys., Chim., Astron., (1996) 322(2) 131-143;

A. S. C. Chan et at, Chem. Ind.(Dekker) (1994) 53(Catalysis of OrganicReactions) 49-68;

K. Inoguchi et al, Synlett (1992) (3) 169-78;

G. Webb et at, Catal. Today (1992) 12(2-3) 319-337;

D. Arntz et al; Catal. Met. Complexes (1991) 12(Met. Promoted Sel. Org.Synth.) 161-189;

K. Harada, Asymmetric Synth. (1985) 5, 345-383; and

W. S. Knowles, Acc. Chem. Res.(1983) 16(3) 106-112.

The person skilled in the art will appreciate that the use of oneenantiomer of such chiral catalysts will give one enantiomer (V) or(VI), and use of the other enantiomer will give the other enantiomer.

Some of the suitable catalysts may be generically defined by the formulaP*-cat-P** wherein “cat” is a metal such as rhodium or ruthenium, and P*and P** each independently represents a chiral phosphine moiety,optionally conjoined.

Preferably the catalyst used for reduction of compounds of formula (IV)where R² is O⁻M⁺, is ruthenium based, such as ruthenium complexes ofBINAP and derivatives thereof, such as[(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)rutheniumchloride.

Preferably the catalyst used for reduction of compounds of formula (IV)where R² is OH, is rhodium-based, such as Rh-DUPHOS(1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene-(1,5-cyclooctadien)-rhodium(I) tetrafluoroborate) or Rh-Ferrotane(1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium(I) tetrafluoroborate).

Suitably the hydrogenation of the acid (IV, R² is OH), can be carriedout in the presence of a base such as sodium bicarbonate,cyclohexylamine, isopropylamine, t-butylamine, adamantanamine, or(S)-α-methylbenzylamine. The hydrogenation can be carried out on apreformed salt (IV, R² is O⁻M⁺).

The reaction is suitably carried out in an inert solvent such as anaqueous C₁₋₃ alcohol e.g. aqueous methanol, or C₁₋₃ alcohol e.g.methanol. Other suitable inert solvents include, but is not limited to,tetrahydrofuran, ethyl acetate, tert-butyl methyl ether, α, α,α-trifluorotoluene, methylene chloride or toluene. The reaction iscarried out optionally at an elevated temperature, under a positivepressure of hydrogen.

Suitable temperatures for good yield and selectivity for theruthenium-catalysed hydrogenation has been found to be approximately 60°C., and for the rhodium-catalysed reactions at approximately 20° C.

The skilled chemist will realise that suitable conditions for particularhydrogenations of compounds of formula (IV) can be found by routinemodification of those mentioned herein.

A further aspect of the invention are novel compounds of formula (IV),(V) and (VI), and novel processes, including those mentioned in theExamples.

The invention is illustrated in the following Examples and Preparationssection, but is not limited to these illustrations.

Preparation 1:3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester

Triethylphosphonoacetate (12.0 Kg, 53.5 mol) was added over 30 minutesto a stirred solution of potassium tert-butoxide (7.20 Kg, 64.2 mol) inTHF (118 liters), between 0 and 5° C., under nitrogen. The mixture waswarmed to 25-30° C. where it was stirred for 1 hour and then added over45 minutes to a solution of tert-butyl bromoacetate (11.5 Kg, 59.0 mol)in THF (28 liters), between 0 and 5° C., under nitrogen. The mixture wasstirred at 0-5° C. for 1 hour and then demineralised water (6.1 liters)and ethanol (30 liters) were added. A solution of potassium hydroxide(4.2 Kg, 75.0 mol) in demineralised water (84 liters) was then addedover 2 hours, between −5 and 0° C. The mixture was stirred at −10° C.for 16 hours and then a solution of citric acid (16.5 Kg, 85.8 mol) indemineralised water (32 liters) was added. The mixture was concentratedin vacuo to a volume of 180 liters and then ethyl acetate (90 liters)was added. The organic phase was separated and the aqueous phase wasre-extracted with ethyl acetate (30 liters). The combined organic phaseswere washed with water (30 liters) and then stripped and replaced withcyclohexane by distillation at atmospheric pressure, at a constantvolume of 72 liters. tert-Butylmethyl ether (18 liters) was added andthe mixture was stirred at 20-25° C. for 12 hours and then filtered. Theresidue was washed with a mixture of cyclohexane (16 liters) andter-butylmethyl ether (3.6 liters) then dried in vacuo for 16 hours togive the title compound as a colourless solid (10.0 Kg, 60% yield, 98%pure by HPLC).

¹H-NMR (CDCl₃) δ: 4.20-4.10 (4H, m), 3.49-3.36 (1H, m), 3.00-2.85 (1H,m), 2.72-2.60 (1H, m), 1.20 (9H, s), 1.37-1.27 (6H, m)

EXAMPLE 1 (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid

A solution of 3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester(100 g, 0.32 mol) in THF (300 ml) was added dropwise over 15 min to astirred solution of potassium tert-butoxide (110 g, 0.98 mol) in THF(300 ml), between −10 and −5° C., under nitrogen. The mixture wasstirred at −10° C. for 15 min and then a solution of hydrocinnamaldehyde(46.8 g, 0.35 mmol) in THF (100 ml) was added dropwise over 15 min,between −13 and −8° C. The mixture was stirred at −10° C. for 30 min andthen a solution of citric acid (111 g, 0.58 mol) in demineralised water(500 ml), and ethyl acetate (500 ml), were added. The pH was adjusted topH 4 with aqueous sodium hydroxide solution (50%) and the phases wereseparated. The aqueous fraction was washed with ethyl acetate (500 ml)and the combined organic fractions were washed with saturated sodiumbicarbonate solution (500 ml), citric acid solution (10%, 500 ml) anddemineralised water (500 ml) and then concentrated in vacuo. Theresulting solid was slurried in cyclohexane (470 ml) for 1 hour and thenthe mixture was filtered. The residue was washed with cyclohexane (2×50ml) and dried in vacuo to leave the title compound as a colourless solid(76 g, 81% yield, 99% pure by HPLC).

MS: 289 [(M-H)]⁻

¹H-NMR (CDCl₃) δ: 7.33-7.16 (5H, m), 7.05 (1H, br t), 3.20 (2H, s), 2.89(2H, br t), 2.50 (2H, br dd), 1.41 (9H, s)

EXAMPLE 2 (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenylpentanoic acid

A solution of (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoicacid (5.8 g, 20 mmol) and1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium(I) tetrafluoroborate (7.4 mg, 10 μmol) in methanol (10 ml) was stirredat 20-25° C. for 24 hours, under hydrogen (4 atmospheres, 60 p.s.i.).The mixture was then concentrated in vacuo to leave the title compoundas a yellow oil (5.8 g, 98% conversion, enantiomeric excess=97%, 95%pure by NMR).

¹H-NMR (CDCl₃) δ: 7.30-7.17 (5H, m), 2.85-2.78 (1H, m), 2.66-2.58 (3H,m), 2.37 (1H, br dd), 1.75-1.51 (4H, m), 1.40 (9H, s)

EXAMPLE 3 (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenylpentanoic acidcyclohexylamine salt

A stirred solution of cyclohexylamine (266 ml, 2.32 mol),(E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (688 g,2.37 mol) and[(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)rutheniumchloride (4.4 g, 4.7 mmol) in methanol (6.9 liters) was heated to 60°C., under hydrogen (60 p.s.i.), for 47 hours and then allowed to cool to20-25° C. (enantiomeric excess=88%). The mixture was filtered through afilter aid Celite® and then the solvent was stripped and replaced withacetone by distillation at atmospheric pressure, at a constant volume of4.2 liters. The resulting suspension was cooled to 20-25° C., stirredfor 4 hours and then filtered. The residue was washed with acetone (2× 1liter) and then dried in vacuo at 45° C. for 16 hours to leave the titlecompound as a colourless solid (590 g, 64% yield, enantiomericexcess=98.9%, 97% pure by HPLC).

¹H-NMR (CD₃OD) δ: 7.23-7.09 (5H, m), 3.05-2.98 (1H, m), 2.64-2.56 (3H,m), 2.53 (1H, dd, J 15.2, 7.2 Hz), 2.23 (1H, dd, J 15.2, 7.2 Hz),2.00-1.97, (2H, m), 1.85-1.81 (2H, m), 1.72-1.20 (10H, m), 1.40 (9H, s)

EXAMPLE 4 (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenylpentanoic acidsodium salt

A stirred solution of sodium bicarbonate (28.6 g, 0.34 mol),(E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (100 g,0.34 mol) and[(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)rutheniumchloride (0.63 g, 0.68 mmol) in methanol (750 ml) and water (250 ml) washeated to 60° C., under hydrogen (60 p.s.i.), for 24 hours and thenallowed to cool to 20-25° C. (enantiomeric excess 87%). The mixture wasfiltered through a filter aid Celite® and the solvent was stripped andreplaced with acetonitrile by distillation at atmospheric pressure, at aconstant volume of 500 ml. The resulting suspension was cooled to 20-25°C. and was stirred for 24 hours, then filtered. The residue was washedwith acetonitrile (3×25 ml) and then dried in vacuo at 45° C. for 3hours to leave the title compound as a colourless solid (65 g, 61%yield, enantiomeric excess=94.3%, 95% pure by NMR).

¹H-NMR (CD₃OD) δ: 7.23-7.10 (5H, m), 2.62-2.58 (3H, m), 2.53 (1H, dd, J15.2, 7.6 Hz), 2.22 (1H, dd, J 15.2, 7.6 Hz), 1.74-1.42 (4H, m), 1.40(9H, s)

EXAMPLE 5 (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexyl-2-pentenoicacid cyclohexylamine salt

Potassium tert-butoxide (20.2 g, 0.18 mol) was added portionwise over 10minutes to a solution of 3-(diethoxyphosphoryl)succinic acid1-tert-butyl ester (25.4 g, 82 mmol) in THF (115 ml), at 0° C., undernitrogen. The mixture was stirred at 0° C. for 40 minutes and thencooled to −20° C. A solution of 3-cyclohexylpropan-1-al (11.5 g, 82 mmolin THF (60 ml) was added dropwise over 10 minutes between −20 and −10°C., under nitrogen. The mixture was stirred between −20 and −5° C. for 3hours and then aqueous citric acid (10%, 250 ml) and ethyl acetate (200ml) was added. The organic phase was separated and the aqueous fractionwas washed with ethyl acetate (200 ml). The combined organic fractionswere washed with saturated sodium bicarbonate solution (2×100 ml),aqueous citric acid solution (10%, 100 ml) and demineralised water (100ml) and then concentrated in vacuo. The resulting solid was taken up inethyl acetate (150 ml) and cyclohexylamine (9.4 ml, 82 mmol) was addeddropwise over 5 minutes at 20-25° C. The mixture was stirred at 20-25°C. for 16 hours and then filtered. The residue was dried in vacuo at 40°C. for 4 hours to leave the title compound as a colourless solid (21.7g, 67% yield, 95% pure by NMR).

¹H-NMR (CD₃OD) δ: 6.70 (1H, t, J 7.2 Hz), 3.26 (2H, s), 3.10-3.00 (1H,m), 2.76-2.63 (2H, m), 2.19-0.90 (23H, m), 1.41 (9H, s)

EXAMPLE 6 (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid

A solution of(E)-2-[2-(teri-butoxy)-2-oxoethyl]-5-cyclohexyl-2-pentenoic acid (0.74g, 2.5 mmol) and1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium(I) tetrafluoroborate (18 mg, 25 μmol) in methanol (2.5 ml) was stirredat 20-25° C. for 24 hours, under hydrogen (4 atmospheres, 60 p.s.i.).The mixture was then concentrated in vacuo to leave the title compoundas a yellow oil (0.74 g, 98% conversion, enantiomeric excess=95%, 95%pure by NMR).

¹H-NMR (CDCl₃) δ: 2.82-2.76 (1H, m), 2.60 (1H, br dd), 2.37 (1H, br dd),1.70-1.60 (6H, m), 1.51-1.30 (3H, m), 1.42 (9H, s), 1.23-1.11 (6H, m),0.96-0.80 (2H, m)

EXAMPLE 7 (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid

A solution of (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenylpentanoic acid(2.2 g, 7.5 mmol) and 5% rhodium on carbon (0.22 g) in methanol (220 ml)was stirred at 20-25° C., under hydrogen (10 atmospheres, 150 p.s.i.)for 24 hours and then filtered through celite. The filtrate wasconcentrated in vacuo to leave the title compound as an oil (2.0 g, 89%yield, 95% pure by NMR).

¹H-NMR (CDCl₃) δ: 2.82-2.76 (1H, m), 2.60 (1H, br dd), 2.37 (1H, br dd),1.70-1.60 (6H, m), 1.51-1.30 (3H, m), 1.42 (9H, s), 1.23-1.11 (6H, m),0.96-0.80 (2H, m)

EXAMPLE 8 (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acidcyclohexylamine salt

(R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-phenylpentanoic acidcyclohexylamine salt (691 g, 1.77 mol) and ethyl acetate (7.0 liters)were added to an aqueous solution of citric acid (10%, 6.3 liters) andthe organic phase was separated, washed with water (7.0 liters) andconcentrated in vacuo to a yellow oil. A solution of the oil and 5%rhodium on carbon (51.6 g) in methanol (7.0 liters) was stirred at20-25° C., under hydrogen (10 atmospheres, 150 p.s.i.) for 48 hours andthen filtered through celite. To the filtrate was added cyclohexylamine(202 ml, 1.77 mol) and the methanol solution was stripped and replacedwith methylethyl ketone by distillation at atmospheric pressure, to avolume of 5.5 liters. The mixture was allowed to cool to 20-25° C. whereit was stirred for 48 hours and then filtered. The residue was washedwith methylethyl ketone (2×500 ml) and then dried in vacuo at 45° C. for4 hours to leave the title compound as a colourless solid (495 g, 71%yield, 99% pure by HPLC).

¹H-NMR (CD₃OD) δ: 3.06-2.99 (1H, m), 2.63-2.56 (1H, m), 2.53 (1H, dd, J15.2, 7.2 Hz), 2.23 (1H, dd, J 15.2, 7.2 Hz), 2.02-1.97 (2H, m),1.77-1.15 (21H, m), 1.43 (9H, s), 0.93-0.82 (2H, m)

EXAMPLE 9 (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acidsodium salt

(R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-phenylpentanoic acidcyclohexylamine salt (6.8 g, 17 mmol) and ethyl acetate (100 ml) wereadded to an aqueous solution of citric acid (10%, 100 ml) and theorganic phase was separated and washed with water (100 ml). Iso-propylalcohol (20 ml) and 5% rhodium on alumina (51.69) were added and themixture was stirred at 20-25° C., under hydrogen (10 atmospheres, 150p.s.i.) for 48 hours and then filtered through celite. To the filtratewas added a solution of sodium hydroxide (0.67 g, 17 mmol) in water andthe mixture was stripped and replaced with acetonitrile by distillationat atmospheric pressure to a volume of 30 ml. The mixture was allowed tocool to 20-25° C. and was stirred for 24 hours. The mixture was cooledto 0° C. and then filtered. The residue was washed with acetonitrile(2×10 ml) and then dried in vacuo at 45° C. for 2 hours to leave thetitle compound as a colourless solid (3.8 g, 69% yield, 95% pure byNMR).

¹H-NMR (CD₃OD) δ: 2.62-2.57 (1H, m), 2.53 (1H, dd, J 14.8, 7.2 Hz), 2.23(1H, dd, J 14.8, 7.2 Hz), 1.76-1.18 (15H, m), 1.44 (9H, s), 0.93-0.82(2H, m)

Preparation 2 Sodium1-hydroxy-3-(2-methyl-1,1′-biphenyl-4-yl)-1-propanesulfonate

A stirred solution of 4-bromo-2-methyl-1,1′-biphenyl (20 g, 81 mmol),allyl alcohol (14 ml, 0.20 mol), tetrabutylammonium chloride (22 g, 81mmol), sodium bicarbonate (17 g, 0.20 mol), palladium(II)acetate (0.91g, 4.0 mmol) and tri-o-tolylphosphine (2.5 g, 8.1 mmol) in acetonitrile(200 ml) was heated to reflux for 1 hour, under nitrogen, and thencooled. Ethyl acetate (200 ml) was added and the mixture was washed withwater (2×200 ml), aqueous citric acid solution (10%, 100 ml) and brine(100 ml). Magnesium sulphate (20 g) and charcoal (2 g) were added andthe mixture was filtered and concentrated in vacuo to an oil. The oilwas taken up in methanol (100 ml) and a solution of sodium metabisulfite(11.2 g) in water (20 ml) was added dropwise, over 10 min. The resultingmixture was stirred at 20-25° C. for 16 hours and then filtered. Theresidue was washed with ethyl acetate (3×20 ml) and dried in vacuo toleave the title compound as a solid (15.9 g, 42% yield, 95% pure byNMR).

¹H-NMR (DMSO) δ: 7.49-7.30 (5H, m), 7.11-7.04 (3H, m), 5.26 (1H, br d),3.84-3.78 (1H, m), 2.81-2.70 (1H, m), 2.20 (3H, s), 2.12-1.99 (1H, m),1.85-1.74 (1H, m)

EXAMPLE 10(E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-2-pentenoicacid cyclohexylamine salt

A solution of potassium tert-butoxide (6.6 Kg, 59 mol) in THF (22liters) was added over 1 hour to a stirred solution of sodium1-hydroxy-3-(2-methyl-1,1′-biphenyl-4-yl)-1-propanesulfonate (4.55 Kg,13.8 mol) and 3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester(4.94 Kg, 15.9 mol) in THF (5.2 liters) and tert-butanol (18.3 liters),from −5 to 0° C., under nitrogen. The mixture was stirred from −5 to 0°C. for 4 hours and then a solution of citric acid (12.0 Kg, 62 mol) indemineralised water (28 liters) was added in one portion. The pH wasadjusted to pH4-5 by the addition of aqueous sodium hydroxide solution(40%) and the organic phase was separated. The organic phase wasconcentrated in vacuo to a volume of approximately 25 liters and thenrecombined with the aqueous phase. Ethyl acetate (28 liters) was addedand the organic phase was separated and then washed with a solution ofsodium bicarbonate (3.18 Kg) in demineralised water (45 liters).Demineralised water (15 liters) was added and the pH was adjusted to pH4-5 by the addition of a solution of citric acid (2.27 Kg) indemineralised water (23 liters). The organic phase was separated, washedwith demineralised water (14 liters) and then azeotropically dried bydistillation at atmospheric pressure at a constant volume of 56 liters.The reaction was cooled to 35 to 40° C. and cyclohexylamine (1.10 Kg,11.1 mol) was added in one portion. The mixture was cooled to 20-25° C.and was stirred for 18 hours. The mixture was then cooled to 0° C., andwas stirred for 2 hours and then filtered. The residue was washed withethyl acetate (5 liters), then dried in vacuo at 40-45° C. to leave thetitle compound as a colourless solid (4.1 Kg, 61% yield, 89% pure byHPLC).

¹H-NMR (CDCl₃) δ: 7.42-7.30 (5H, m), 7.16 (1H, d, J 7.6 Hz), 7.15-7.05(2H, m), 6.83 (1H, t, J 7.2 Hz), 3.29 (2H, s), 2.50-2.43 (2H, m), 2.263H, s), 2.03-1.98 (2H, m), 1.78-1.71 (2H, m), 1.61-1.57 (1H, m), 1.44(9H, s), 1.30-1.10 (5H, m)

EXAMPLE 11(E)-2-[2-(terl-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-2-pentenoicacid adamantanamine salt

A solution of potassium phosphate tribasic (160 g, 0.762 moles) indemineralised water (500 ml) was added over 15 minutes to a stirredslurry of sodium1-hydroxy-3-(2-methyl-1,1′-biphenyl-4-yl)-1-propanesulfonate (125 g,0.381 moles) in toluene (1500 ml) and demineralised water (1000 ml). Themixture was stirred at 20-25° C. for 16 hours. The organic phase wasseparated and the aqueous phase was extracted with toluene (100 ml). Thecombined organic extracts were washed with demineralised water (1000ml), and the solution was azeotropically dried by distillation oftoluene at 40° C. under reduced pressure. The volume of solution wasreduced to 250 ml, and allowed to cool to 20-25° C. Meanwhile,3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester (112 g, 0.360moles) was added portionwise over 10 minutes to a solution of sodiumteri-butoxide (114 g, 1.175 moles) in toluene (1120 ml) at −10° C. undernitrogen. The mixture was stirred for 30 minutes at −10° C. The toluenesolution prepared previously was added over 45 minutes between −10° C.and 0° C. The mixture was stirred at −10° C. for 1 hour and aqueouscitric acid solution (10% w/v, 1000 ml) was added. The biphasic mixturewas stirred at 20-25° C. for 16 hours. The organic phase was separatedand washed with demineralised water (1000 ml). The organic phase wasazeotropically dried by distillation at 40° C. under reduced pressure ata constant volume of 1330 ml. The solution was maintained at 40-45° C.,and a solution of adamantanamine (53 g, 0.350 moles) in toluene (665 ml)was added in one portion. The mixture was cooled to 20-25° C., and wasstirred for 16 hours. The precipitate was collected by filtration,washed with toluene (150 ml) and dried in vacuo at 50° C. to leave thetitle compound as a colourless solid (153 g, 76% yield).

¹H-NMR (CDCl₃) δ: 7.42-7.05 (8H, m), 6.91 (1H, t, J 7.2 Hz), 3.29 (2H,s), 2.79-2.71 (2H, m), 2.52-2.43 (2H, m), 2.25 (3H, s), 2.08 (3H, s),1.81 (6H s), 1.65 (6H s), 1.42 (9H, s),

EXAMPLE 12(E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-2-pentenoicacid sodium salt

A solution of potassium tert-butoxide (7.25 g, 64.6 mmol) in THF (24 ml)was added over 1 hour to a stirred solution of sodium1-hydroxy-3-(2-methyl-1,1′-biphenyl-4-yl)-1-propanesulfonate (5.0 g,15.2 mmol) and 3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester(5.5 g, 17.7 mmol) in THF (6 ml) and tert-butanol (30 ml), between −5and 0° C., under nitrogen. The mixture was stirred between −5 and 0° C.for 4 hours and then a solution of citric acid (13.2 g) in demineralisedwater (132 ml) was added in one portion. The pH was adjusted to pH4-5 bythe addition of aqueous sodium hydroxide solution (40%) and the organicphase was separated. The organic phase was concentrated in vacuo andthen recombined with the aqueous phase. Ethyl acetate (55 ml) was addedand the organic phase was separated and then washed with a solution ofsodium bicarbonate (3.5 g) in demineralised water (50 ml). The organicphase was separated and washed with citric acid (5.0 g) in demineralisedwater (50 ml), demineralised water (50 ml) and then concentrated invacuo to an orange oil. The oil was taken up in acetonitrile (30 ml) anda solution of sodium bicarbonate (0.65 g, 4.1 mmol) in demineralisedwater (5 ml) was added. The solution was azeotropically dried bydistillation at a constant volume of acetonitrile and the mixture wasgranulated at 20-25° C. overnight. The mixture was filtered and theresidue dried in vacuo at 45° C. to give the title compound as a whitesolid (2.6 g, 43% yield, 95% pure by NMR).

¹H-NMR (CDCl₃) δ: 7.38-7.21 (5H, m), 7.10 (1H, d, J 7.6 Hz), 7.05 (1H,s), 7.02(1H, d J 7.2 Hz), 6.89 (1H, t, J 7.2 Hz), 3.30 (2H, s),2.70-2.65 (2H, m), 2.47-2.41 (2H, m), 2.19 (3H, s), 1.40 (9H, s).

EXAMPLE 13(R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-pentanoicacid

A solution of(E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-2-pentenoicacid (3.8 g, 10 mmol) and1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium(I) tetrafluoroborate (7.8 mg, 10 μmol) in methanol (10 ml) was stirredat 20-25° C. for 24 hours, under hydrogen (60 p.s.i.). The mixture wasthen concentrated in vacuo to leave the title compound as a yellow oil(3.8 g, 98% conversion, enantiomeric excess=95%, 95% pure by NMR).

¹H-NMR (CDCl₃) δ: 7.42-7.30 (5H, m), 7.18-7.03 (3H, m), 2.94-2.82 (1H,m), 2.70-2.62 (3H, m), 2.41 (1 H, br dd), 2.23 (3H, s), 1.80-1.59 (4H,m), 1.43 (9H, s)

EXAMPLE 14(R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-pentanoicacid cyclohexylamine salt

A stirred solution of(E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-2-pentenoicacid cyclohexylamine salt (1.1 Kg, 2.3 mol) and[(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)rutheniumchloride (2.2 g, 2.4 mmol) in methanol (8.2 liters) and water (2.8liters) was heated to 60° C., under hydrogen (60 p.s.i.), for 40 hoursand then allowed to cool to 20-25° C. (enantiomeric excess=88%). Themixture was concentrated in vacuo to a volume of 3 liters and then ethylacetate (5 liters) was added. The mixture was distilled at constantvolume of ethyl acetate until water droplets appeared in the distillate.The mixture was then cooled to 20-25° C. and then demineralised water(2.9 liters) and citric acid (485 g, 2.5 mol) were added. The organicphase was separated and washed with demineralised water (1.1 liter) andthen dried azeotropically by distillation at a constant volume of 8.25liters. Methylethyl ketone (8.25 liters) was added and the mixture waswarmed to 40° C. Cyclohexylamine (228 g, 2.28 mol) was added in oneportion and the mixture was allowed to cool to 20-25° C., then wasstirred for 16 hours. The mixture was filtered and the residue waswashed with a mixture of ethyl acetate (55 ml) and methylethyl ketone(55 ml) and then dried in vacuo at 45° C. to leave the title compound asa colourless solid (0.71 Kg, 65% yield, enantiomeric excess=98.6%, 99%pure by HPLC).

¹H-NMR (CDCl₃) δ: 7.42-7.25 (5H, m), 7.11 (1H, d, J 7.6 Hz), 7.08-7.00(2H, m), 2.90-2.82 (1H, m), 2.67-2.58 (4H, m), 2.30 (1H, br dd), 2.23(3H, s), 2.00-1.86 (2H, m), 1.80-1.50 (7H, m), 1.41 (9H, s), 1.38-1.09(5H, m)

EXAMPLE 15(R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-pentanoicacid (S)-alpha-methylbenzylamine salt

(R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-pentanoicacid can be enantiomerically upgraded as the (S)-alpha-methylbenzylaminesalt. Thus,(R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methyl-1,1′-biphenyl-4-yl)-pentanoicacid cyclohexylamine salt (50 g, 0.10 mol, enantiomeric excess=72%) waspartitioned between ethyl acetate (750 ml) and aqueous citric acidsolution (10%, 750 ml). The organic phase was separated, washed withwater (500 ml), then azeotropically dried by distillation at constantvolume. (S)-alpha-methylbenzylamine (13.2 ml, 0.10 mol) was addeddropwise over 5 min at 40° C., the mixture was allowed to cool to 20-25°C., and was then stirred for 24 hours. The mixture was filtered and theresidue was washed with ethyl acetate (100 ml) and then dried in vacuo)at 45° C. for 2 hours to leave the title compound as a colourless solid(41.0 g, 91% yield, enantiomeric excess=96.4%, 95% pure by NMR).

¹H-NMR (CDCl₃) δ: 7.40-7.22 (10H, m), 7.12 (1H, d, J 7.6 Hz), 7.06-7.02(2H, m), 4.22-4.18 (1H, m), 2.80-2.76 (1H, m), 2.63-2.59 (3H, m), 2.34(1H, dd, J 16.4, 5.6 Hz), 2.24 (3H, s), 1.77-1.70 (3H, m), 1.61-1.56(1H, m), 1.47 (3H, d, J 6.8 Hz), 1.40 (9H, s)

What is claimed is:
 1. A process for the preparation of a compound ofthe formula (V) or (VI)

wherein R is aryl, C₃₋₈ cycloalkyl, C₁₋₁₀ alkyl, (aryl)C₁₋₁₀ alkylene,(C₃₋₈ cycloalkyl)C₁₋₁₀ alkylene, heterocyclyl, (heterocyclyl)C₁₋₁₀alkylene, (aryl)C₃₋₈ cycloalkylene, (C₃₋₈ cycloalkyl)arylene or (C₁₋₁₀alkylaryl)C₁₋₁₀ alkylene, wherein aryl is a mono- or bicyclic partiallyor fully unsaturated carbocyclic ring system containing from 4 to 10atoms, wherein aryl is a mono- or bicyclic partially or fullyunsaturated carbocyclic ring system is phenyl or naphthyl, or apartially or fully unsaturated mono- or bicyclic heterocyclic moietyhaving up to 10 atoms in the ring system and with up to 4 hetero-atomsin the said ring system each independently selected from N, O and S,said carbocyclic ring system and heterocyclic moiety being optionallysubstituted by one or more substituents each independently selected fromhalogen, NO₂, NH₂, CO₂R⁹, phenyl, C₁₋₆ alkyl(optionally substituted byone or more halogen), and C₁₋₆ alkoxy(optionally substituted by one ormore halogen), and wherein heterocyclyl is a 3- to 8-membered mono orbicyclic saturated heterocyclic group having from 1 to 4 ringhetero-atoms each independently selected from N, O and S, optionallysubstituted by one or more substituents each independently selected fromhalogen, NO₂, NH₂, CO₂R⁹, phenyl, C₁₋₆ alkyl(optionally substituted byone or more halogen), and C₁₋₆ alkoxy(optionally substituted by one ormore halogen); R¹ is C₁₋₆ alkoxy; R² is OH or O⁻M⁺, wherein M⁺ is ametal cation is sodium, lithium, potassium or a protonated amine moietyselected from the group consisting of mono(C₁₋₁₀ alkyl)ammonium,di(C₁₋₁₀ alkyl)ammonium, tri(C₁₋₁₀ alkyl)ammonium, mono(C₃₋₁₀cycloalkyl)ammonium, di(C₃₋₁₀ cycloalkyl)ammonium, tri(C₃₋₁₀cycloalkyl)ammonium, (C₁₋₁₀ alkyl)_(n1) (C₃₋₁₀ cycloalkyl)_(n2)ammonium,anilinium, benzylammonium, triethanolammonium, and(S)-α-methylbenzylammonium, where n1 and n2 are each independentlyselected from 1 or 2 with the proviso that the sum of n1 and n2 is notgreater than 3; R⁹ is H or C₁₋₆ alkyl; comprising (A) reacting analdehyde of formula RCHO, or a protected derivative thereof selectedfrom the group consisting of a hemiacetal or adduct thereof wherein saidadduct is a bisulphite, wherein R is as defined above, with a phosphoruscompound of formula (IX)

or a metal carboxylate salt thereof, selected from the group consistingof a sodium, lithium or potassium carboxylate salt thereof, wherein R¹is as defined above, and wherein P is a phosphonate moiety of formula—P(O)(OR³)(OR⁴), wherein R³ and R⁴ are each independently selected fromH, C₁₋₆ alkyl, benzyl and phenyl (optionally substituted by one or moreC₁₋₆ alkyl), or R³ and R⁴ taken together are C₂₋₅ alkylene, or P is aphosphorane moiety of formula —(PR⁵R⁶R⁷)⁺X⁻ wherein R⁵, R⁶ and R⁷ areeach independently selected from C₁₋₆ alkyl and phenyl, and X isbromine, chlorine or iodine, in the presence of a sodium, lithium orpotassium C₁-C₆ alkoxide base, in an inert solvent, and at a temperatureof from −80° C. to 20° C. to form a compound of the formula (IV)

and (B) asymmetric reduction of the compound of formula (IV) to form thecompound of formula (V) or (VI).
 2. The process according to claim 1,wherein said asymmetric reduction comprises hydrogenation.
 3. Theprocess according to claim 1, wherein the catalyst used for reduction ofcompounds of formula (IV) where R² is O⁻M⁺, is ruthenium based.
 4. Theprocess according to claim 3, wherein the catalyst used is a rutheniumcomplex of BINAP or a derivative thereof.
 5. The process according toclaim 4, wherein the catalyst is[(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)rutheniumchloride.
 6. The process according to claim 1, wherein the catalyst forreduction of compounds of formula (IV) where R² is OH is rhodium-based.7. The process according to claim 6, wherein the catalyst is Rh-DUPHOS(1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene-(1,5-cyclooctadien)-rhodium(I) tetrafluoroborate), or Rh-Ferrotane(1,1′-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium(I) tetrafluoroborate).
 8. The process according to claim 2, wherein thehydrogenation of the compound of formula IV when R² is OH is carried outin the presence of a base.
 9. The process according to claim 8, whereinthe base is selected from the group consisting of sodium bicarbonate,cyclohexylamine, isopropylamine, t-butylamine, adamantanamine and(S)-α-methylbenzylamine.
 10. The process according to claim 2, whereinhydrogenation is carried out on the preformed salt of formula IV whereinR² is O⁻ M⁺.
 11. The process according to claim 3, wherein thehydrogenation is carried out in an inert solvent and under a positivepressure of hydrogen.
 12. The process according to claim 11, wherein thesolvent is an aqueous C₁₋₃ alcohol or a C₁₋₃ alcohol.
 13. The processaccording to claim 3, where the reaction is carried out with aruthenium-based catalyst and the reaction temperature is approximately60° C.
 14. The process according to claim 6, where the reaction iscarried out with a rhodium-based catalyst and the reaction temperatureis approximately 20° C.